The hepatic function of cholesterol sulfotransferase 2B1b (SULT2B1b)in energy met
胆固醇磺基转移酶2B1b(SULT2B1b)在能量代谢中的肝功能
基本信息
- 批准号:9087207
- 负责人:
- 金额:$ 33.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acetate-CoA LigaseAcetylationAlkanesulfonatesBindingBreedingCholesterolDataDown-RegulationEatingEnergy MetabolismEnzymesEventExclusionFastingFeedbackGene ExpressionGene TargetingGenesGluconeogenesisGoalsHealthHepaticHepatocyteHomeostasisHumanIn VitroInsulin ResistanceLeptinLiverMetabolicMetabolic DiseasesMetabolic syndromeMetabolismModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusNuclearNuclear TranslocationObese MiceObesityOxygen ConsumptionPlayProductionRegulationRoleSULT2B1TestingTherapeutic AgentsTransgenesTransgenic MiceTransgenic OrganismsXenobioticsbasecholesterol sulfotransferasecholesteryl sulfatefeedingglucose metabolismimprovedin vivoinsulin sensitivitylipid metabolismmeetingsnew therapeutic targetoverexpressionpromotersulfationsulfotransferase
项目摘要
DESCRIPTION (provided by applicant): The cholesterol sulfotransferase SULT2B1b is a cytosolic sulfotransferase best known for its activity in sulfonating cholesterol and oxysterols. Metabolic syndrome, often manifested as obesity and insulin resistant type 2 diabetes, is a major health concern. The dysregulation of glucose and lipid metabolism plays an important pathogenic role in obesity and type 2 diabetes. Although the activity of SULT2B1b in catalyzing the sulfation of cholesterol has been documented, the role of SULT2B1b and its enzymatic byproduct cholesterol sulfate (CS) in energy metabolism and metabolic syndrome remains largely unknown. Our preliminary results showed that: 1) SULT2B1b was induced in obese mice and during the transition from the fasted to the fed state; 2) SULT2B1b and CS inhibited gluconeogenesis in hepatic cells; 3) SULT2B1b and CS specifically inhibited the gluconeogenic activity of HNF4α; 4) Treatment with CS inhibited gluconeogenesis and improved insulin sensitivity in both HFD and ob/ob models; 5) Transgenic overexpression of SULT2B1b improved metabolic functions in the HFD model; 6) Leptin is a potential effector for the metabolic benefit of SULT2B1b; 7) SULT2B1b and CS suppressed the expression of acetyl-coenzyme A synthetase 2 (Acss2), decreased the acetylation of HNF4α, and caused the nuclear exclusion of HNF4α; whereas a forced expression of Acss2 abolished the inhibitory effect of CS on HNF4α; 8) Down-regulation of HNF4α abolished the inhibitory effect of CS on gluconeogenesis in vitro; and 9) SULT2B1b is a potential HNF4α target gene, providing a possible mechanism of negative feedback regulation of gluconeogenesis. Based on our preliminary data, we hypothesize that the cholesterol sulfotransferase SULT2B1b has a previously unrecognized role in inhibiting gluconeogenesis and alleviating metabolic disease. Mechanistically, the metabolic benefit of SULT2B1b may have been achieved through its enzymatic byproduct cholesterol sulfate (CS) and by targeting the acetylation and nuclear translocation of the gluconeogenic transcriptional factor HNF4α. We also hypothesize that the SULT2B1 is a HNF4α target gene, which represents a negative feedback mechanism to limit the gluconeogenic activity of HNF4α. We anticipate that leptin is a potential effector of SULT2B1b in improving metabolic functions. By using the liver-specific SULT2B1b transgenic mice, in conjunction with HFD and ob/ob models of obesity and type 2 diabetes, we propose three Specific Aims to test our hypotheses: 1) To determine whether the liver-specific overexpression of SULT2B1b inhibits the ob/ob model of obesity and type 2 diabetes; 2) To determine the molecular mechanism by which SULT2B1b and CS inhibit gluconeogenesis; and 3) To determine whether the induction of SULT2B1b by HNF4α represents a potential mechanism of negative feedback regulation of gluconeogenesis. To our knowledge, this study represents the first attempt to comprehensively evaluate the endobiotic and hepatic function of SULT2B1b and its enzymatic byproduct CS in energy metabolism in vivo. Results from this study may establish SULT2B1b as a novel therapeutic target and CS as a therapeutic agent to manage metabolic disease.
描述(由适用提供):胆固醇磺胺硫代酶Sult2b1b是一种胞质磺胺转移酶,以其在硫化胆固醇和氧甲醇中的活性而闻名。代谢综合征通常表现为肥胖症和胰岛素2型糖尿病,这是一个主要的健康问题。葡萄糖和脂质代谢的失调在肥胖症和2型糖尿病中起重要的致病作用。尽管已经记录了Sult2B1b在催化胆固醇硫酸化中的活性,但Sult2B1b及其酶副产物硫酸胆固醇(CS)在能量代谢和代谢综合征中的作用仍然很少。我们的初步结果表明:1)在肥胖小鼠和从禁食到美联储状态的过渡期间,SULT2B1B是诱导的; 2)SULT2B1B和CS抑制肝细胞中的糖异生; 3)SULT2B1B和CS特别抑制了HNF4α的糖原性活性; 4)用CS治疗HFD和OB/OB模型,抑制了糖异生和提高胰岛素敏感性; 5)SULT2B1B的转基因过表达改善了HFD模型中的代谢功能; 6)瘦素是SULT2B1B代谢益处的潜在效应子; 7)SULT2B1B和CS抑制乙酰辅酶A合成酶2(ACSS2)的表达,发展为HNF4α的乙酰化,并引起HNF4α的核排除;而ACSS2的强制表达消除了CS对HNF4α的抑制作用; 8)HNF4α的下调消除了CS对体外葡萄糖发生的抑制作用; 9)SULT2B1B是一种潜在的HNF4α靶基因,提供了葡萄糖发生负反馈调节的可能机制。根据我们的初步数据,我们假设胆固醇磺胺硫代硫代酶Sult2b1b在抑制糖异生和减轻代谢疾病方面具有先前未认识到的作用。从机械上讲,SULT2B1B的代谢益处可能是通过其酶促副产品胆固醇(CS)以及靶向糖原性转录因子HNF4α的乙酰化和核易位来实现的。我们还假设Sult2B1是HNF4α靶基因,它代表了限制HNF4α糖原活性的负反馈机制。我们预计瘦素是Sult2B1b改善代谢功能的潜在效应因子。通过使用实时特异性SULT2B1B转基因小鼠,与HFD和OB/OB/OB/OB/OB/OB/OB/OB/OB/OB/OB/OB/OB/OB模型一起,我们提出了三个特定的目的,以测试我们的假设:1)确定SULT2B1B的肝脏特异性过表达是否抑制SULT2B1B的OB/OB/OB/OB/OB/OB/OB模型的观察和2型透射蛋白二个透射蛋白; 2)确定sult2b1b和cs抑制葡萄糖发生的分子机制; 3)确定HNF4α诱导SULT2B1B是否代表了葡萄糖发生负反馈调节的潜在机制。据我们所知,这项研究代表了SULT2B1B及其酶促代谢中Sult2B1b及其酶促副产物CS的首次尝试。这项研究的结果可能会将Sult2B1B作为一种新型治疗靶靶标,而CS作为治疗代谢疾病的治疗剂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Wen Xie其他文献
Wen Xie的其他文献
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{{ truncateString('Wen Xie', 18)}}的其他基金
Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity
外源性受体介导环境对人类疾病和发病率的影响
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10411925 - 财政年份:2019
- 资助金额:
$ 33.5万 - 项目类别:
PXR-Mediated Xenobiotic Response in the Pathogenesis Hemorrhagic Shock
失血性休克发病机制中 PXR 介导的异生素反应
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10302289 - 财政年份:2019
- 资助金额:
$ 33.5万 - 项目类别:
Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity
外源性受体介导环境对人类疾病和发病率的影响
- 批准号:
10194495 - 财政年份:2019
- 资助金额:
$ 33.5万 - 项目类别:
Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity
外源性受体介导环境对人类疾病和发病率的影响
- 批准号:
10623308 - 财政年份:2019
- 资助金额:
$ 33.5万 - 项目类别:
The hepatic function of cholesterol sulfotransferase 2B1b (SULT2B1b)in energy met
胆固醇磺基转移酶2B1b(SULT2B1b)在能量代谢中的肝功能
- 批准号:
8754531 - 财政年份:2014
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8895932 - 财政年份:2014
- 资助金额:
$ 33.5万 - 项目类别:
A Novel Regulation of the Phase II Enzyme Estrogen Sulfotransferase
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9265092 - 财政年份:2014
- 资助金额:
$ 33.5万 - 项目类别:
A Novel Regulation of the Phase II Enzyme Estrogen Sulfotransferase
II 期酶雌激素磺基转移酶的新调控
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9060933 - 财政年份:2014
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